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What is sepsis?

Disease continuum with progression of severity.

Long-standing definitions:

Sepsis = systemic inflammatory response syndrome (SIRS) due to confirmed or highly suspected infection.In veterinary patients sepsis is most often due to bacterial infection. Often gram-negative; their endotoxin (lipopolysaccharide) is a very potent trigger of inflammation. Mixed infections and gram-positive infections also described.

Severe sepsis = sepsis that results in organ or body system dysfunction.Cardiovascular system often first concern. Patient with systemic hypoperfusion and confirmed/highly suspected infection has severe sepsis.Other organs and systems may also be affected.

Septic shock = patient with hypoperfusion or hypotension that is refractory to intravenous fluid resuscitation.

SEPSIS-3 definitions:

Recently suggested updates in human medicine.Work done by Task Force convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.

New definitions:

Sepsis = life-threatening organ dysfunction due to a dysregulated host response to infection

Still early days; not without critics and problems. Need to be prospectively evaluated and potentially adapted.

All much less clear in veterinary medicine!

Sepsis management:

Early goal directed therapy (EGDT):

Introduced by Emmanuel Rivers with publication of a single centre trial in The New England Journal of Medicine in 2001.Randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit.Ultimately concluded that early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.Since then many other studies have been published that apparently also identified outcome benefits.

In sepsis circulatory abnormalities lead to an imbalance between systemic oxygen delivery and oxygen demand.Abnormalities include intravascular volume depletion, peripheral vasodilatation, myocardial depression, and increased metabolism.Result is global tissue hypoxia or shockPhysiologically, aim of management is to adjust cardiac preload, afterload, and contractility to optimise tissue oxygen delivery.

EGDT became well known and many people supported its use.Presumptively extrapolated as gold standard best practice to veterinary medicine too. Though few able to deliver this care due to practical and resource (expertise, equipment, financial, personnel) limitations.

Some critiqued the Rivers study and the EGDT approach. E.g. not widely adopted in Australasia.

Surviving Sepsis Campaign:

First set of "Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock" published in 2004.SSC administered jointly by the European Society of Intensive Care Medicine, International Sepsis Forum, and the Society of Critical Care Medicine.

Objective:

"to develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis."

ProCESS (USA), ARISE (Australasia), ProMISe (UK):

Three large scale multicentre randomised controlled trials published recently. Reported that human sepsis mortality at an all-time lowConcluded that in a general population of human patients with severe sepsis and septic shock, EGDT did not confer a mortality benefit compared with usual resuscitation.Ability to generalise from these studies – including to veterinary medicine – depends on consistency of treatment provided as part of usual resuscitation across individual hospitals.

Again there have been critiques of these three recent trials.

Bottom line for veterinary practice:

If we are able to deliver a high level of standard care we will be doing right by our patients. The aspects of management that are now being emphasised are ones that we should also be able to do well.

So what does that mean?

Early recognition of patients that are septic or at high risk of becoming septic

Especially signs of systemic cardiovascular compromise, hypoperfusion, hypotension, possibly full blown shockMajor cause of hyperdynamic distributive shock in dogs; but some dogs with sepsis have a hypodynamic picture.Cats classically have hypodynamic picture

Not every septic patient is pyrexic. Temperature may be inappropriately ‘normal’, or hypothermic.

Lactate:

Complex relationship between sepsis and blood lactateInappropriately high lactate for given cardiovascular/perfusion status possible flag for sepsis.Not every septic patient has notable hyperlactataemia

So intravascular volume resuscitation involves using a replacement isotonic crystalloid with a bolus strategy.Less aggressive approach advocated in recent times due to increasing recognition of harms of excessive fluid administration/over-resuscitation.Again, extrapolated to veterinary practice.

Albumin:

Natural colloidHas been used extensively in human sepsis managementCanine albumin still not widely available and using human albumin in dogs and cats creates additional risks.

Early use of inopressor agents:

Hypoperfusion in sepsis due to hypovolaemia, peripheral vasodilation and myocardial depressionIn addition to volume replacement, early inopressor use makes sense to squeeze vessels (especially venous capacitance) and boost cardiac pumpNoradrenaline (norepinephrine) current agent of choice in human medicine where available and affordable. Albeit not total consensus.Extrapolated by some to veterinary practice.

Dopamine fallen out of favour in human medicine due to negative risk-benefit assessment.

Starting intravenous antibiosis early:

Early aggressive antibiosis justified in patients with confirmed sepsis.Likewise in patients with suspected sepsis. But must be reasonable and think critically in terms of index of suspicion. Not carte blanche to adopt ‘just in case’ approach in all patients!Antibiotics massively overused in veterinary and human medicine. Significant bacterial resistance challenges.

Broad-spectrum, including gram-negative coverage where involvement suspectedDo not withhold until samples collected for microbiology; but do collect samples for microbiology!

Looking for sources of infection. And establishing control of the source of infection as well as possible as soon as possible:

Prioritise resuscitation, stabilisation and maintenance of stabilityIdentifying focus of infection may involve e.g. good thorough physical examination, point of care ultrasound, diagnostic imaging, and/or collection of fluid and cell samples.In some patients antibiotics and own immune system will be curativeIn other cases other interventions are required (e.g. exploratory laparotomy; abscess drainage).Some early though non-definitive source control may be possible with modern non-invasive techniques

Close regular monitoringAnd tailored goals that make sense for the individual patient.

Urine output can also help to inform perfusion status and response to treatment.Urinary catheter placement not recommended in all patients with confirmed/suspected sepsis:Foreign bodyCarries risk of ascending potentially resistant hospital-acquired infectionCauses patient discomfortPlacement may require sedationHelpful when present though.

Glycocalyx

What is the glycocalyx?

Gel-like acellular epithelial layer endothelium of blood vessels (and part of heart, lymphatics)Important in fluid dynamics and various pathophysiological statesMeshwork of glycoproteins, proteoglycans and various soluble moleculesIn a dynamic equilibrium with adjacent flowing bloodConstantly changing in thickness and composition; sheds and regenerates

What are the functions of the glycocalyx?

1) Key determinant of vascular permeability:

Integrity important for normal microvascular fluid exchangeDisrupted by inflammatory cells and cytokines, and ischaemia-reperfusionIncreases vascular permeability leading to oedemaHallmarks of SIRS and sepsis as well as other disease statesUbiquitous nature of glycocalyx helps explain why localised infection can have widespread consequences.

2) Mechanical protection for endothelium3) Creates a microenvironment for receptor binding, local growth and repair. Protects the vascular wall.

What is the relevance of all this?

Traditional Starling model of vascular fluid exchange has been revised.

"In the last 5 years or so, we have had a better understanding of capillary fluid dynamics, particularly in conjunction with an appreciation of the glycocalyx. We now know that the glycocalyx normally ‘traps’ about a litre and half of plasma water in it (due to its hydrophilic chemical composition!) and that normally in the capillaries, there is a central moving layer of plasma and a relatively immobile layer closer to the endothelium….the bit that is bound to the glycocalyx. This explains the differences in measured capillary and venous hematocrit values, and also why Crystalloid : Colloid equivalence is 1.3 : 1 rather than 4: 1 as previously thought.

We have also acquired a better understanding of the mechanisms of edema formation in critical illness and more importantly, the magical phenomenon of improved diuresis that we have all marvelled at, during the recovery phase.

In short, we have kinda debunked the original Starling theory of fluid dynamics in the capillary.

We now know that the colloid osmotic pressure in the intravascular space will only oppose the outward movement of water, and increasing the colloid osmotic pressure by synthetic colloids will not reverse the flow and draw fluid from the interstitial to the intravascular space. ( Multiple trials , starting with the SAFE trial have proved the futility of using synthetic colloids !) What they end up doing is, probably drawing water from the glycocalyx in the intravascular space itself and dehydrating and then disintegrating this vital layer. As a result you will find a transient improvement in blood pressures, but afterwards, a lot of this fluid will track into the extravascular space. Any hyperosmolar solution can do this including Soda Bicarb….we have all seen the very transient increase in blood pressure after bicarb which has always been incorrectly attributed to ‘reversal of acidosis’…bah!!

Extravasation of fluid from the capillaries is predominantly dependant on capillary hydrostatic pressure and not on decreased intravascular colloid osmotic pressure— because we have realised that interstitial and intravascular colloid osmotic pressures are very close to each other.

The way to prevent overloading and thus extravasation would be to minimise rapid increases in capillary hydrostatic pressure. How can we do that? – By small volume crystalloid boluses and early use of alpha1 agonists—the latter work by afferent arteriolar constriction and thus minimising huge increases in capillary hydrostaic pressures. This is where Marik’s argument takes a strong foothold.

Albumin is needed for the integrity of glycocalyx, — explaining why albumin is making a comeback into our fluid armamentarium.

The lymphatics have assumed a pivotal role in the normal mechanisms that prevent edema formation. We have realised that they are a very active conduit to return of interstitial fluid to the central circulation, and they they have contractile collecting ducts and passages that are calcium dependant. They are inhibited by the terrible twins ANP and BNP—therefore shutting down in active sepsis, where the twins tend to dominate. (This also partly explains the peripheral edema commonly seen with Ca channel blockers when they are used as antihypertensives). Once the sepsis resolves, ANP and BNP levels drop and the lymphatics recover their contractile elements. All the interstitial fluid can now be returned to the central circulation causing an improved diuresis.

In any case, fluids should only be used as any other drug should be— only if needed. We need to realise that fluid requirement and fluid responsiveness are two completely different things and focus on appropriate fluid balance rather than branding it as either restrictive or liberal." (John, retired human intensivist)

Does this affect how we manage our patients clinically, and if so, how?Can the glycocalyx serve as a novel therapeutic target?

At present, mostly discussion and theorisingRecognition of the glycocalyx and its complexity helps to:Better understand the pathophysiology of sepsisExplain some of what we see in clinical patientsExplain why no single magic bullet has been found for the treatment of sepsis; too complex for this.

Sepsis damages the glycocalyx. Management should aim to minimise further damage, e.g.